Biosynchronous transdermal drug delivery

ABSTRACT

Systems and methods for synchronizing the administration of compounds with the human body&#39;s natural circadian rhythms and addiction rhythms to counteract symptoms when they are likely to be at their worst by using an automated and preprogrammable transdermal or other drug administration system.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/746,704, filed Jun. 22, 2015, which is a continuation of U.S. patentapplication Ser. No. 14/162,156 filed Jan. 23, 2014, now abandoned,which is a continuation of U.S. patent application Ser. No. 11/162,517filed Sep. 13, 2005, now abandoned, which claims the benefit of U.S.Provisional Application No. 60/609,418 filed Sep. 13, 2004 which areincorporated herein by reference.

This application also relates to PCT application No. PCT/IB2004/002947entitled Transdermal Drug Delivery Method and System filed Sep. 13, 2004which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates, in general, to controlled drug deliverymethods and systems, and, more specifically, to systems and methods forbisynchronous transdermal drug delivery in which drugs, pharmaceuticals,and other bioactive substances are delivered transdermally into a bodyin a manner that is synchronized with biological processes and/orbiological rhythms so as to improve performance of the substance in thebody.

RELEVANT BACKGROUND

In the field of drug delivery, it is recognized that supplying the drugin a correct temporal pattern is an important attribute of any drugdelivery methodology. Controlled release drug delivery systems areintended to improve response to a drug and/or lessen side effects of adrug. The term “controlled release” refers generally to deliverymechanisms that make an active ingredient available to the biologicalsystem of a host in a manner that supplies the drug according to adesired temporal pattern. Controlled release drug delivery may beimplemented using instantaneous release systems, delayed releasesystems, and sustained release systems. In most cases, controlledrelease systems are designed to maintain a sustained plasma level of anactive ingredient in a drug within a human or animal host over a periodof time.

Instantaneous release refers to systems that make the active ingredientavailable immediately after administration to the biosystem of the host.Instantaneous release systems include continuous or pulsed intravenousinfusion or injections. Such systems provide a great deal of controlbecause administration can be both instantaneously started and stoppedand the delivery rate can be controlled with great precision. However,the administration is undesirably invasive as they involveadministration via a puncture needle or catheter. ‘Delayed release’refers to systems in which the active ingredient made available to thehost at some time after administration. Such systems include oral aswell as injectable drugs in which the active ingredient is coated orencapsulated with a substance that dissolves at a known rate so as torelease the active ingredient after the delay. Unfortunately, it isoften difficult to control the degradation of the coating or encapsulantafter administration and the actual performance will vary from patientto patient. Sustained Release generally refers to release of activeingredient such that the level of active ingredient available to thehost is maintained at some level over a period of time. Like delayedrelease systems, sustained release systems are difficult to control andexhibit variability from patient to patient. Due to the adsorptionthrough the gastrointestinal tract, drug concentrations rise quickly inthe body when taking a pill, but the decrease is dependent on excretionand metabolism, which cannot be controlled. In addition, the adsorptionthrough the gastrointestinal tract in many cases leads to considerableside effects (such as ulcers), and can severely damage the liver.

Transdermal drug delivery has developed primarily for sustained releaseof drugs in situations where oral sustained release systems areinadequate. In some cases, drugs cannot be effectively administeredorally because the active ingredients are destroyed or altered by thegastrointestinal system. In other cases the drug may be physically orchemically incompatible with the coatings and/or chelating agents usedto implement sustained release. In other cases a transdermal deliverysystem may provide sustained release over a period of days or weekswhereas orally administered drugs may offer sustained performance overonly a few hours. A wide variety of active substances can be deliveredthrough transdermal systems so long as the active substance can beprovided in a form that can cross the skin barrier.

In most cases transdermal delivery systems are passive, taking the formof a patch that is adhesively attached to the host. The patch includes aquantity of the active substance, along with a suitable carrier if needbe, absorbed in a sponge or similar system. Once applied, the activeingredient diffuses into the host through the skin at a rate determinedby the concentration of the active substance and the diffusivity of theactive substance. However, a variety of physical and chemical processesat the skin/patch boundary affect the delivery rate and may eventuallyinhibit drug delivery altogether. Active transdermal delivery systemshave been developed to help regulate the delivery rate by providingmechanisms to improve drug delivery over time by “pumping” the activeingredient. One such system is described in U.S. Pat. No. 5,370,635entitled “DEVICE FOR DELIVERING A MEDICAMENT” which describes a systemfor delivering a medicament and dispensing it to an organism for arelatively long period of time, for example at least a few days. Thedevice can be adapted for positioning on the surface of the skin of ahuman or possibly an animal body in order to apply a medicament theretofrom the outer side thereof.

Conventional transdermal systems circumvent the disadvantages of theadsorption through the gastrointestinal tract, but they do not optimizeor tailor the dosing regimen to offset peak symptoms. In addition theconstant transdermal delivery of a drug can lead to severe side effects,including debilitating sleep disorders and ever increasing tolerance.

Timed delivery is most often used to maintain a sustained level of adrug in the body. A significant focus of current research in drugdelivery has been to determine the influence of a patient's circadian orother biological rhythms on drug efficacy and efficiency. This researchdemonstrates that certain disease symptoms follow a daily pattern, withpeak symptoms at certain times of the day. It has been widelyacknowledged that hormones, neurotransmitters and other intra-bodycompounds are released in different amounts at different times of theday pursuant to daily patterns. The Wall Street Journal reported on May27, 2003 that “Doctors are increasingly looking at the clock when itcomes to prescribing medicine, instructing patients not only to whatdrug to use but also precisely when to take it. The new approach stemsfrom a growing body of research that demonstrates that certain diseasestend to get worse at certain times of the day. By synchronizingmedications with a patient's body clock, many physicians believe thatthe drugs will work more effectively and with fewer side effects. Insome cases, the improvements have been so pronounced that doctors havebeen able to reduce dosages.” Similarly, American Pharmacy reports that“Circadian physiologic processes alter drug absorption, distribution,metabolism, and excretion. As a result, drug doses need to be adjustedto meet the differing needs of target organs or tissues at various timesof the day.” See, L. Lamberg, American Pharmacy, 1991; N831(11): 20-23.Doctors have responded to this growing body of research by prescribing acarefully timed drug administration regimen to optimize treatment.

Recently, an orally administered drug for arthritis treatment hassuggested a chronotherapeutic approach using a delay release systemwhere the delay is scheduled to release the active ingredient at thebeginning of an interleukin 6 cascade that is believed to cause earlymorning stiffness in rheumatoid arthritis patients. By attempting tosynchronize the drug delivery with a biological cycle it is believedthat low doses may be used to achieve desired results. However, thissystem does not overcome the limitations of delayed release systemsdescribed above. Although it is possible to meet the requirements ofchronopharmacology with pills, this requires an enormous amount ofdiscipline by the patient to comply with the treatment regimen. Asillustrated above, to achieve optimal results, many patients may need towake up during the night to take their medication.

Hence, what is needed is a reliable means of delivering multiple drugsin precisely timed and measured doses-without the inconvenience andhazard of injection, yet with improved performance as compared toorally-delivered drugs.

Currently, patient compliance (taking the proper dosages at theprescribed times) is a critical problem facing caregivers andpharmaceutical firms alike. Studies show that only about half ofpatients take medications at the times and in the dosages directed bytheir physician. It is reported that each year, 125,000 deaths and up to20% of all hospital and nursing home admissions result from patientnon-compliance. It is estimated that non-compliance results inadditional healthcare costs in excess of $100 billion per year in UnitedStates. These figures are even more pronounced for the elderly. Hence, aneed exists for systems and methods that increase patient compliance foradministration of a variety of drugs.

Additional advantages and novel features of this invention shall be setforth in part in the description that follows, and in part will becomeapparent to those skilled in the art upon examination of the followingspecification or may be learned by the practice of the invention. Theadvantages of the invention may be realized and attained by means of theinstrumentalities, combinations, compositions, and methods particularlypointed out in the appended claims.

SUMMARY OF THE INVENTION

Briefly stated, the present invention involves synchronizing theadministration of compounds with the human body's natural circadianrhythms and addiction rhythms to counteract symptoms when they arelikely to be at their worst by using an automated and pre programmabletransdermal or other drug administration system.

Specifically, this invention describes a method to maximize theefficiency of compound administration, decrease negative side effectsand increase the efficacy of pharmacological therapy by synchronizingand tailoring the administration of certain compounds to match thesecircadian rhythms.

Thus based on an analysis of the human body's circadian rhythms, theinvention delivers varying dosages at varying times, pursuant to apreprogrammed dosage profile. This ensures that peak drug concentrationsare present in the bloodstream to offset peak disease and addictionsymptoms arising from variances and fluctuation in the body's naturalcircadian rhythms. Further, these methods ensure that less of a drug isin the bloodstream when disease and addiction symptoms are at theirlowest.

The present invention describes methods for treating diseases,addictions and disorders in humans. These methods involve synchronizingand tailoring the administration of compounds with the body's naturalcircadian rhythms to counteract symptoms when they are likely to be attheir worst by using an automated and pre programmable transdermal drugadministration system.

More specifically, these methods synchronize and tailor drugadministration to the human body's circadian rhythms to deliver varyingdosages at varying times. This ensures that peak drug concentrations arepresent in the bloodstream to offset peak disease and addiction symptomsarising from variances and fluctuation in the body's natural circadianrhythms. Further, these methods ensure that less of a drug is in thebloodstream when disease and addiction symptoms are at their lowest.This minimizes negative side effects, and increases efficacy of thedosing regimen.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an exemplary device useful for implementing the presentinvention;

FIG. 2A and FIG. 2B illustrate comparative drug release profilesdemonstrating operation of the present invention;

FIG. 3 is a schematic illustration of a drug delivery device inaccordance with the present invention;

FIG. 4 is a schematic illustration of an alternative drug deliverydevice in accordance with the present invention;

FIG. 5 shows an exemplary administration profile for a stimulantdelivery system;

FIG. 6 shows an exemplary administration profile for a nicotine deliverysystem;

FIG. 7 shows an exemplary administration profile for a nitroglycerinedelivery system tailored to treat variant angina attacks; and

FIG. 8 illustrates an exemplary administration profile for anitroglycerine delivery system tailored to treat stress-induced anginaattack.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The reality of circadian rhythms in animals including humans is wellknown. Biological rhythms are periodic fluctuations in biologicalcharacteristics over time, which also include circadian as well asseasonal variations. Circadian, or approximately 24-hour, rhythmsinclude the production of biological molecules such as cortisol andadrenaline, the regulation of body temperature and heart rate, changesin characteristics of blood, such as stickiness, and behaviors such aswakefulness, sleep and periods of activity.

Research demonstrates that certain disease symptoms follow a dailypattern, with peak symptoms at certain times of the day. It has beenwidely acknowledged that hormones, neurotransmitters and otherintra-body compounds are released in different amounts at differenttimes of the day pursuant to daily patterns. It is believed that thefailure of current transdermal systems to synchronize drugadministration with the body's natural rhythms often lead to (i) severeside effects, including debilitating sleep disorders (in the context ofnighttime nicotine administration, for example), (ii) ever increasingtolerance (in the case of nitroglycerin and other pharmaceuticals forexample), (iii) more expensive therapies, since more of a compound isneeded since body rhythm tailored dosing is not implemented. Inaddition, many addictions follow a daily pattern consistent with one'scircadian rhythms. For example, according to studies performed,immediately upon waking, smokers have peak nicotine cravings. These peakcravings return after each meal, due to the interplay of serotoninrelease as a trained response to the culmination of a meal. Our methodsprecisely time the administration of drugs so that they reach peaklevels when symptoms are likely to be at their worst, and efficacy isgreatly improved.

The present invention involves precisely timing the administration ofdrugs so that they reach peak levels in synchronization with times whensymptoms are likely to be at their worst, or times at which the drugsare believed to be more effective in the body and/or better tolerated bythe patient. The present invention is described in terms of a particularexample drug delivery system that provides automated and precise controlover dosing, with single-dose capability, (once while people sleep) orcapability to administer separate and varying-sized doses many timesthroughout a multiple day period. The particular implementation isconsistent with a commercial development of a miniaturized, automatedand programmable non-invasive drug delivery system called theChronoDose™ system being developed by the assignee of the presentinvention. The system enables controlling of the amount of drug exposedto the skin in a controlled time dependent way according to a programmedadministration schedule that implements a desired dosage profile. Inthis manner the present invention enables one to precisely control andvary the time of drug release and the amount of each dose, pursuant toan easily set preprogrammed dosage profile.

Research demonstrates that for certain symptoms, conditions anddiseases, drug effects can be optimized when administered in a defined(and often varying) dosage at predefined times. This is known asChrono-Pharmacology. To illustrate the importance of Chrono-Pharmacologyconsider the following facts:

Asthma attacks are 100 times more likely between 4:00 and 6:00 AM.

Heart attacks and strokes are most likely to occur around 6:00 AM.

Variant Angina attacks occur 30 times more often in the middle of thenight between 2:00 AM and 4:00 AM.

Smokers experience the highest cravings immediately upon waking up.

Lethargy and difficulty getting out of bed is highest immediately uponwaking up early in the morning.

Cold and flu symptoms peak during night time and early morning hours,when cold medications are wearing off.

In accordance with the present invention, substances with proven orsuspected chrono-pharmacological efficiency are integrated into aminiaturized, automated, programmable watch-like device, such as device100 shown in FIG. 1. The delivery system 100 shown in FIG. 1 can be usedfor a variety of active compositions, and is small, fully automated andprogrammable. This system consists of a re-usable wristwatch-like device101 to control the time and dosage of drug delivery; and a small,disposable, ‘reservoir’ 103, which is about the size of a quarter or ½dollar coin in a particular example, that the user can simply pop-in toplace on the watch-like platform. This reservoir patch lasts, forexample, up to 72 hours, depending on the application. Shorter andlonger reservoir lifetimes are contemplated. The device is readilyadapted to be worn on the forearm, ankle, or other convenient bodylocation.

In a particular application the replaceable reservoir can include adescription of an administration schedule that can be used to manuallyor automatically program device 100 with an administration schedule. Forexample, written schedule can be printed on or affixed to the reservoir101 or electrically programmed using volatile or non-volatile memory. Inthis manner a dosing profile can be prescribed and filled by a pharmacyin much the same manner as a conventional drug prescription is handledtoday.

An exemplary implementation shown in FIG. 3 comprises a collapsible drugreservoir, an expandable waste reservoir, a micro-pump, electronics forautomation, a display, and a highly permeable membrane. An exemplarysystem is described in PCT application No. PCT/IB2004/002947 entitledTRANSDERMAL DRUG DELIVERY METHOD AND SYSTEM filed Sep. 13, 2004 which isincorporated herein by reference. The drug reservoir will contain about3 ml of drug formulation. A tiny, miniaturized pump is activated atpreprogrammed times and releases a predefined amount of drug formulationinto the drug chamber, where the formulation comes into contact withhighly permeable membrane. This membrane rests on the skin, and providesfor even diffusion of the drug over the device's drug absorption surfacearea. This membrane works effectively with, and can be coated with, anadhesive. In operation, when the administration of the drug needs to bediscontinued, the remaining drug formulation is either removed from themembrane area via a waste chamber, containing a hydrophilic substance(hydrogel) or the device is taken off.

In an implementation shown in FIG. 4, a pressurized drug reservoir isused which minimizes or eliminates need for a micropump. Electronicscontrol a valve that allows controlled quantities of the drug to beapplied to the drug chamber where the formulation comes into contactwith highly permeable membrane.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is known. See, for example, U.S. Pat. No.5,370,635 entitled “DEVICE FOR DELIVERING A MEDICAMENT” the disclosureof which is incorporated herein by reference. Such patches may beconstructed using a saturated media, pressurized reservoirs, orunpressurized reservoirs with micropumps for continuous, pulsatile, oron-demand delivery of an active material. For example, apharmaceutically acceptable composition of an active material may becombined with skin penetration enhancers including, but not limited to,oleic acid, amino acids, oleyl alcohol, long chain fatty acids,propylene glycol, polyethylene glycol, isopropanol, ethoxydiglycol,sodium xylene sulfonate, ethanol, N-methylpyrrolidone, laurocapram,alkanecarboxylic acids, dimethylsulfoxide, polar lipids,N-methyl-2-pyrrolidone, and the like, which increase the permeability ofthe skin to the active material and permit the active material topenetrate through the skin and into the bloodstream. Pharmaceuticallyacceptable compositions may be combined with one or more agentsincluding, but not limited to, alcohols, moisturizers, humectants, oils,emulsifiers, thickeners, thinners, surface active agents, fragrances,preservatives, antioxidants, vitamins, or minerals. Pharmaceuticallyacceptable compositions may also be combined with a polymeric substanceincluding, but not limited to, ethylcellulose, hydroxypropyl cellulose,ethylene/vinylacetate, polyvinyl pyrrolidone, and the like, to providethe composition in gel form, which may be dissolved in solvent such asmethylene chloride, evaporated to the desired viscosity, and thenapplied to backing material to provide a patch. The backing can be anyof the conventional materials such as polyethylene, ethyl-vinyl acetatecopolymer, polyurethane and the like.

Example substances include caffeine and a variety of over-the-counterand prescription stimulants (for treating fatigue, sleep disorders,attention deficit disorders and a variety of other conditions), nicotine(for smoking cessation), nitroglycerin (for treating heart attack andstrokes), fentanyl (for treating chronic pain), albutamol (for treatingasthma), and selegiline (for treating depression, attention deficitdisorder or Parkinson's disease). We have carefully identified thesespecific drugs and diseases because they have the following attributes:(i) Chrono-Pharmacology is critical to optimized dosing but is not beingimplemented because no automated transdermal system exists, and (ii)these drugs can be transdermally absorbed passively (i.e., without theneed for ultrasound or electrical stimulation or other permeationenhancers). Exemplary chrono-pharmacological systems that can make useof the present invention are summarized in Table 1.

DISEASES/CONDITION CHRONOPHARMACOLOGY Morning Lethargy Adrenaline islowest in the morning, making waking uncomfortable and difficult formany people. This can be treated by administering OTC Stimulant beforewaking Smoking Cessation Nicotine at night creates sleeping disorders(nightmares), but cravings are the highest after waking up. This can betreated by administering Nicotine before waking up. Angina Angina(variant) attacks occur 30 (thirty) times more often between 2:00 a.m.and 4:00 a.m. This can be treated by administering larger nitroglycerindoses in early morning Asthma Asthma attacks are 100 times more likelybetween 4:00 a.m. and 6:00 a.m. Adrenaline and Cortisol are virtuallyabsent at night. This can be treated by administering albutamol in earlymorning Colds and Flu Heaviest symptoms overnight and in the morning.This can be treated by administering Cold/Flu medicine during the night.Heart Attacks and Strokes Heart attacks and strokes are most likelybetween 6:00 a.m. and Noon. This can be treated by administeringAnticoagulants before waking up. Pain Neurological pain is worst between3 A.M and 8 A.M. This can be treated by administering pain medicationduring sleep. Depression Selegiline at night can create sleepingdisorders (nightmares), but depression symptoms are high immediatelyupon waking up. This can be treated by administering Selegiline beforewaking up. Rheumatoid Arthritis Worst upon awakening. Cortisol andanti-inflammatory hormones are very low at night. This can be treated byadministering medication delivered before waking up. SupplementsVitamins and supplements are best administered in low doses over thecourse of the day to be most effective.

Using this system the present invention can pre-program the times andamount of each dosage by precisely controlling the amount of drugexposed to the skin during each dosing. This feature is advantageouswhen a drug is best administered during sleep, e.g., 1 to 2 hours beforewaking up. The present invention precisely counteracts peak diseasesymptoms and increase patient compliance.

The present invention represents the first true non-invasivechrono-pharmacological drug delivery device. While current transdermalapplications are restricted to the dosage profile shown in FIG. 2A, theautomated implementation of the present invention can be programmed fora variety of drug delivery patterns to achieve customized patient dosingregiments for optimal therapy (FIG. 2B). There are many advantages for acontrolled transdermal release of an active material such as a drug. Asused herein, the term ‘controlled’ or ‘sustained’ release of an activematerial includes continuous or discontinuous, linear or non-linearrelease of the active material according to a programmed schedule. Amongthe advantages of controlled release are the convenience of a singleapplication for the patient, avoidance of peaks and valleys in systemicconcentration which can be associated with repeated injections, thepotential to reduce the overall dosage of the active material, lowerbody stress, and the potential to enhance the pharmacological effects ofthe active material. A lower, sustained dose can also prevent adverseeffects that are occasionally observed with infusion therapy. Inaddition to significantly reducing the cost of care, controlled releasedrug therapy can free the patient from repeated treatment orhospitalization, thus offering the patient greater flexibility andimproving patient compliance. A controlled release formulation ofcertain drugs also provides an opportunity to use the drug in a mannernot previously exploited or considered. The present invention isparticularly advantageous when (i) known chrono-pharmacologicalinformation shows that a drug's effects can optimized when administeredin a defined dosage at a predefined time or times, and/or (ii) patientcompliance with the dosing regimen is greatly increased due toautomation, (doses required at inopportune times, when sleeping, forexample).

A device according to the present invention in general comprisesdispensing means, e.g., a pump, at least one drug reservoir, at leastone administration element (patch reservoir, administration reservoir,administration compartment, administration chamber) and at least onesolvent removal and/or recovery element and if necessary control meansinterconnected to each other. In a preferred embodiment of the inventionthe administration reservoir and the solvent recovery means areincorporated in an administration unit (patch). The at least one drugreservoir contains a sufficient amount of one or more active substancedissolved or dispersed at an appropriate concentration in a formulationwhich may contain a solvent or a solvent mixture that is volatile. Ifappropriate other excipients, for example tissue permeation promoters(enhancers), thickening substances, solubilizers, buffers, chemicalstabilizers, preservatives are present too.

The active substance may be any dispensable fluid (for example a liquid,gel or powder), although liquids are particularly of use in thedispensing unit. In some embodiments, at least one of the reservoirs maycontain an active substance in powder or other dry form. The powder orother agent is dispensed from the reservoir, and may be combined with asolvent and/or another liquid such as a penetration enhancer. Ifappropriate the dispensing unit may allow chemical reactions to occur,e.g., in the administration reservoir, as well as phase changes tostabilize (such as a change from a solid to a liquid state).

In operation the formulation contained in the at least one drugreservoir is dispensed by the dispensing unit into the at least oneadministration reservoir (patch reservoir). Volume and frequency ofadministration of the active substance are controlled by a control unitwhich preferably is freely programmable according to given needs. Thesolvent recovery means reclaim solvent that was dispensed together withthe formulation into the patch reservoir and is not absorbed. Thepreferably volatile solvent evaporates from the interface continuouslyand is guided to the solvent recovery means. If appropriate a heatingelement or other helping means may be used for supporting evaporation ofthe solvent. However the temperature of the skin in general issufficient. The solvent recovery means serve to remove depleted solventfrom the interface such that, e.g., after repeated dispensing, activesubstance concentration maintains at a certain concentration and nounwanted substance is accumulated within the device. Upon quittingdispensing of formula, the residual solvent is recovered and dryness ofthe interface is achieved, which results in controlled termination ofdrug delivery. Alternatively or in addition depleted solvent may bedischarged into environment only, e.g., by direct evaporation.

In general the active substance is completely enclosed in theadministration/patch reservoir and is not in contact with theenvironment or other components. The interface may comprise a membrane(polymer membrane) which may be lined with an absorbent material, suchas blotting paper, suitable to receive active substance and facinginwards to the interior of the device. The membrane of the interface isin functional contact with the surface to be treated. The drugformulation is dispensed onto the interface by the dispensing unit whichis interconnected to the drug reservoir. The solvent recovery means arenormally arranged at a certain distance from the absorbent materialpreventing uncontrolled absorption of solvent. The volume and frequencyof dispensing are freely programmable and are used to control thedelivery rate and the time pattern of delivery of the drug.

Drug is delivered from the interface primarily by diffusion. The solventrecovery element reclaims the solvent that was dispensed with theformulation onto the interface and was not absorbed otherwise. Thesolvent recovery element preferably is located within the device andcomprises one or more desiccants and/or general adsorbents such assilica gel, molecular sieves or active carbon. These materials arenormally arranged within a bag consisting of non-wettable but vaporpermeable material e.g., such as GoreTex®. In a preferred embodiment thesolvent recovery element is arranged close to but in non-contact withthe interface. The volatile solvent evaporates from the interfacecontinuously under the influence of body heat and the vapors are trappedin the solvent recovery element. The solvent recovery element serves thepurpose of removing depleted solvent from the interface so that, afterrepeated dispensing, drug concentration maintains its highest value andno freely moving liquid is formed within the device. Upon quittingdispensing of drug formula, the residual solvent is recovered anddryness of the interface is achieved, which brings about stoppage ofdrug delivery. The solvent recovery element is contained in anon-wettable material in order to avoid uptake of drug formula andconsequent loss of drug.

Several parameters are relevant for the amount of active substanceabsorbed by the surface to be treated such as concentration of theactive substance in the solvent, the repetition-rate of supply and thevolume supplied. These parameters are controllable by the describedinvention.

Solvent that is not absorbed by the skin in a sufficient way is carriedoff in another way than by absorption through the skin, e.g., byevaporation into the environment and/or by absorption by another means,e.g., absorbing substance such as silica gel. By this it is possible toavoid negative decrease of the concentration of active substance due toaccumulation of the solvent which would impact the diffusion ratethrough the skin. Especially solvents based on water and/or alcohol arehaving at temperatures nearby the temperature of skin a vapor pressurewhich is sufficiently high to carry off the solvent by evaporation.However, the carrying off and/or diffusion rate of the solventpreferably is adjusted to the diffusion rate of the active substancethrough the skin to avoid accumulation of the solvent or precipitationof the active substance on the skin in a negative way.

The described invention offers the opportunity to precisely control therate and the time pattern of systemic drug delivery. It can be appliedto the delivery of drug into and/or across the skin. With themethodology according to the present invention the amount of activesubstance delivered per unit of time can be adjusted to values rangingbetween zero and a known maximum, the moments of time can be defined atwhich the delivery rate is set to a predetermined value and the deliveryof drug over time spanning hours or days can be regulated in aprogrammed manner, e.g., using real time control. A device suitable tocarry out the described technology offers the opportunity of fullyautomated transdermal drug delivery.

The method most widely used in prior art for automated controlledtransdermal delivery is iontophoresis. With this method control ofdelivery of a drug is achieved by an electric current which is appliedto the skin. By adjusting the current the delivery rate of the drug isregulated. Advantages of the present invention over iontophoresis arethe ability to completely turn off delivery or reduce the delivery ratebelow a minimal value corresponding to passive skin permeation, theabsence of skin irritation that the electric current may cause whenapplied to the skin and the low energy consumption compared toiontophoresis because normally no high currents are needed for extensiveperiods of time.

Conventional patch based delivery systems as known from prior artcomprising a patch and a therewith interconnected dispensing unit aremore or less suitable to administrate a chemical substance under aspecific time regime, where the quantity of the specific dose deliveredto the patch can be predetermined more or less accurate and each timeperiod of dispensing the substance can be predetermined as well.However, turning delivery to a patch as known from prior art on and offcauses uncontrolled time lag in the delivery rate to or through theskin. The delivery systems known from prior art often lead to aconstantly diminishing dispensing rate. These problems are avoided bythe present invention.

The disclosed invention offers a combination of formula dispensing withan on- and off-turning delivery of the formula and a simultaneoussolvent recovery for the purpose of maintaining a constant and high drugdelivery rate. The achievable delivery rate and the time lag due to on-and off-events result from the interplay between the rate of formuladispensing and the rate of solvent recovery. The former is preferablycontrolled by a freely programmable pump and the latter by amount andquality of the material of the solvent recovery element.

Precise control of delivery of the active substance is very important.Related thereto is the precise control of the solvent. The solvent maybe controlled by additional means e.g., as described as follows.

A solvent removal system comprises a waste reservoir which isinterconnected by a waste valve, e.g., a pinch valve, and/or a wastepump to the administration reservoir. In the case of a pin valve thewaste valve preferably is driven by utilizing a wire made out ofShape-Memory-Alloy (SMA) or an alternative device pursuant to apreprogrammed regimen. In a given example the waste valve is opened orthe waste pump is turned on such that the solvent is removed and e.g.,brought in contact to a desiccant such that the solvent is safelyabsorbed. Proper administration may be achieved by opening and closingthe connection to the waste reservoir by an appropriate time regime. Incertain applications it is helpful to switch the connection to the wastereservoir with a certain delay with respect to the administration of theactive substance. Instead or in addition to a pinch valve a micro pumpmay be appropriate to pump excessive solvent into a waste reservoir. Ina further embodiment the tubing e.g., for depletion of solvent cancomprise absorbent material which thereby is brought into direct contactwith depleted carrier solution. It is possible to remove depleted fluideither pursuant to a preprogrammed profile or systematically, e.g.,depleted fluid is brought into contact every 20 minutes with desiccant,by using a small lever or arm, or otherwise made to come into directcontact with the depleted carrier solution, resulting in absorption ofthe depleted carrier solution. Alternatively, a waste reservoir, e.g., asponge, is lowered by a small lever or arm or otherwise to come intodirect contact with the depleted carrier solution, resulting inimmediate absorption of the depleted carrier solution. In a differentembodiment a selectively permeable membrane surrounds a sponge orabsorbent material, and the selectively permeable membrane primarilyallows the solvent to pass through it (whether due to electric charge ofthe molecule or molecular size or acidity of the solvent vs. the drug orsome other regulating means) and this semi permeable membrane eitherremains in constant contact with the diffusion surface or isperiodically brought in to contact with the diffusion surface using anabove described method. In a further embodiment a sponge or an absorbentmaterial is in contact with the diffusion surface and a pre-tested andtimed capillary action of the sponge is such that depleted carriersolution is absorbed at the right time and in proper amounts as toassist with the achievement of preprogrammed dosage profiles, i.e., eventhough much active substance may be absorbed along with the carriersolution still sufficient drug is present to achieve the objectives.

Modulated dispensing of drug formula brings about a significant increaseof delivery rate over the one-time addition of formula at equal drugconcentration. Thus, maximization of drug delivery rate is achieved.This is because the removal of solvent from the relatively smalldispensed volume creates in situ an increase of drug concentration withsubsequent saturation and precipitation of drug in the interface inimmediate contact with the skin as evidenced by dryness of theinterface. By the herein described method it is possible that thedelivery rate of the active substance can be adjusted using the samedrug solution by changing the dispensed volume of solution. Depending onthe field of application it was found that about 2 gram of desiccant aresufficient for trapping solvent over at least 9 hours when e.g.,dispensing 40 μl/hr of a given drug formula. It was found that increaseof drug concentration in the formula causes a corresponding increase ofdelivery rate for dispensing of e.g., 40 μl/hr but not for e.g., 15μl/hr. Apparently, dryness of the interface for the latter dispensingvolume is achieved far before each consecutive dispensing step, thushampering drug permeation.

Depending on the field of application, solvent removal means may be forexample: a desiccant in a bag, any other absorbent material in a bag, adesiccant/absorbent connected to the interface by a tube, adesiccant/absorbent connected to the interface by a tube which comprisesa valve, a compartment connected to the environment for evaporation, acompartment through which gas is guided to promote evaporation, anabsorbent sponge, an absorbent sponge attached to an arm that moves itto and away from the interface, an absorbent sponge with a gas blowingdevice for drying. The material surrounding the solvent removal meanspreferably is made out of tissue, cloth, membrane, etc. Theadministration device (compartment) may comprise, if appropriate, atleast one sensor, e.g., a humidity sensor for feedback control to thedispenser.

The solvent recovery means serves to remove depleted solvent from theactive area of the administration reservoir such that the activesubstance concentration is maintained at a certain concentration and nounwanted substance is accumulated within the administration device. Uponquitting dispensing of formula into the administration device, theresidual solvent is recovered and dryness of the interface is achieved,which results in controlled termination of drug delivery into skin.Normally the temperature of skin is sufficient to evaporate anddischarge the solvent. However, a heating element or other helping meansmay be used for supporting evaporation.

The solvent recovery means are normally arranged at a certain distancefrom the interface, the administration reservoir respectively, ispreventing uncontrolled absorption of solvent. The separation layer maye.g., comprise or consist of an inert foam or an appropriate cellularmaterial or honeycomb. The solvent recovery means are preferably locatedwithin the administrative device and preferably comprise one or moredesiccants and/or general or selective adsorbents such as silica gel,molecular sieves or active carbon preferably surrounded by anon-wettable material permeable for the vapors of solvent, e.g., such asGore-Tex®.

Subsequent the method will be described in a general manner: The drugformulation is dispensed into the administration reservoir by thedispensing system. The volume and frequency of dispensing are freelyprogrammable and are used to control the delivery rate and the timepattern of delivery of the chemical substance into the skin. Thechemical substance is delivered from the administration reservoir bydiffusion in the skin or onto the surface of the skin. The solventrecovery element reclaims solvent that was dispensed with theformulation into the administration reservoir. The solvent recoveryelement is in close vicinity to but in general not in direct contactwith the administration reservoir to avoid uncontrolled absorption ofsolvent.

The volatile solvent evaporates from the interface under the influenceof body heat and the vapors are trapped by the solvent recovery means,e.g., a chamber filled with absorbing material. The solvent recoveryelement serves the purpose of removing depleted solvent from the patchreservoir so that, after repeated dispensing, drug concentrationmaintains its highest value and no detrimental fluid (liquid) isaccumulated within the administrating device. Upon quitting dispensingof drug formula, the residual solvent is recovered and dryness of theinterface is achieved, which brings about stoppage of drug delivery.

Applications—ArisePatch™

A contemplated consumer product is the ArisePatch™. Most peopleexperience difficulty and discomfort when waking early in the morning.According to a 2002 National Sleep Foundation poll 49% of US adults age18-29 have trouble waking in the morning and 41% of US adults age 30-64have trouble waking in the morning. There are 165,000,000 adults in theUS alone age 18-64, meaning approximately 74,250,000 US adults age 18-64have trouble waking in the morning.

The ArisePatch implementation of the present invention allowsindividuals, while asleep, to have an over-the-counter (OTC) orprescription stimulant automatically administered during a 1-2 hourpre-wake-up period. FIG. 5 illustrates an exemplary stimulantadministration profile showing a blood plasma level of ephedrine innanograms per milliliter on the vertical axis, with time on thehorizontal axis. Stimulant concentrations will reach peak levelsimmediately prior to having to wake. Immediately upon waking up theindividual will be alert and feel well rested. The ArisePatch™ willeliminate the typical discomfort or difficulty associated with gettingup early. This functionality is attractive to employed people getting upfor work to ensure punctuality, and just about anyone who wants tooffset morning discomfort associated with a late night, jet lag, orsickness.

Applications—Smoking Cessation

Nicotine replacement has been the most frequently used therapy tosupport smokers in their effort to quit. Smokers report that the cravingfor a cigarette is greatest immediately upon waking in the morning. Thetime elapsed between wakening and the first cigarette is the bestindicator of addiction. For most smokers this time only a few minutes.

Current nicotine patches cause severe sleep disturbances by releasingnicotine steadily throughout the night to ensure sufficient morningnicotine levels to offset the strong morning craving. It is widelyaccepted that current nicotine patches have a detrimental and commonside effect-sleeping disorders, and insomnia, including persistentnightmares. Therefore, users are often forced to remove the patch in theevening before they go to bed. This eliminates sleep disturbances, butresults in nicotine levels that are insufficient to offset the strongmorning craving. This is a major drawback to current nicotine patchesand many users relapse, resulting in a less efficient smoking cessationtherapy. Current patches present the user with a difficult decision,choosing between nightmares and relief from the strong morning cravings.

An exemplary product contemplated by the present invention is calledNicotine ChronoDose™ system. In accordance with the present invention,the system can begin to administer nicotine (or nicotine analogs or anyother smoking cessation compound including but not limited to Zyban)automatically during a one hour period immediately prior to waking. Thiswill relieve the smoker's peak craving upon waking without causingnightmares and insomnia. We believe that this system clearly provides asuperior method for smoking cessation.

A more advanced nicotine replacement system than that described above isworn for three days at a time and is programmed to release nicotine in adaily rhythmic pattern such as shown in FIG. 6 to offset peaks in asmoker's cravings. FIG. 6 illustrates an exemplary nicotineadministration profile showing a blood plasma level of nicotine innanograms per milliliter on the vertical axis, with time on thehorizontal axis. This implementation will reduce nicotine dependency byadministering pre-programmed levels of nicotine pursuant to typicalsmoking patterns. For instance many smokers report that cravings for acigarette are greatest upon waking up, after lunch, midafternoon, afterdinner and before bedtime. This implementation of the present inventionwill automatically release larger doses of nicotine to offset peakcravings and no nicotine when cravings are typically at a minimum. Thepresent invention may be delivered in a preprogrammed manner for eachtreatment regimen. The only involvement by the user will be thereplacement of the ‘reservoir’ every three days, and the replacement ofthe platform housing as needed.

This implementation represents a tremendous move forward in nicotinereplacement therapy, and is far superior to the old-technology systemsthat simply release the same amount of nicotine all day and night. Withthe present invention, one can systematically decrease a smoker'stolerance without increasing dependence (the result of a constant flow)and better wean a smoker off nicotine. This will allow the smoker tobetter ‘tailor-down’ and decrease the amount of nicotine he needs toquit. Modern smoking cessation is much more than nicotine replacementtherapy. Programs also include weight control, diet and psychologicalsupport. The present invention fits well into these programs, since itaddresses the key component of being able to quit smoking by efficientlycountering the withdrawal symptoms while doing away with the negativeside effects of current nicotine replacement therapy systems, namelysleep disturbance.

Applications—Cold and Flu Treatment

Cold and flu symptoms are worst from midnight until the early morningbecause the concentration of cortisol is lowest at that time. Currentnight time cold and flu medication end up losing efficacy by earlymorning when cold and flu symptoms are highest. Therefore peoplesuffering from a cold or flu are often unpleasantly awoken by anincrease in symptoms, cutting sleep short. Set and put on beforebedtime, the present invention will automatically deliver a larger doseof medication and immuno-boosters in the early morning hours to moreeffectively combat the peak cold and flu symptoms that occur in themorning. Users will experience less severe cold and flu symptoms duringthe morning hours, will not have their sleep cycle cut short, and willwake up feeling symptom-free. This implementation uses prescription orOTC cold medicine alone or optionally in combination with certaintransdermally efficacious vitamins and immune system boosters to providea total solution to cold and flu ailments. This is the first coldtherapy that combines OTC medicine with supplemental immuno-boosters ina comprehensive and automated manner. Our system will treat the coldsymptoms directly and boost the body's immune system to help it healnaturally.

In a particular application, the Cold and Flu automated transdermal drugdelivery system utilizes OTC cold medicine, Vitamin C, Echinacea, andZinc to provide a total solution to cold and flu ailments, and all whileyou sleep. Cold and flu symptoms are worst in the middle of the nightand early morning because the hormone cortisol, a key inflammationfighter, is missing at that time. Cold and flu symptoms are worst frommidnight until the early morning because the concentration of cortisolis lowest at that time. Current night time cold and flu medication endup losing efficacy by early morning when cold and flu symptoms arehighest. Therefore people suffering from a cold or flu are oftenunpleasantly awoken by an increase in symptoms, cutting sleep short

Set and put on before bedtime, the Cold and Flu automated transdermaldrug delivery system utilizes our proprietary technology toautomatically deliver a larger dose of medication and immuno-boosters inthe early morning hours to more effectively combat the peak cold and flusymptoms that occur in the morning. Users will experience less severecold and flu symptoms during the morning hours, will not have theirsleep cycle cut short, and will wake up feeling symptom-free.

Our system not only combats statistically proven peak nighttime andearly morning cold symptoms by releasing OTC cold medicine, but actuallyhelps your body to heal by boosting its immune system through Vitamin C,Echinacea and Zinc supplementation in small but distinct doses all nightlong.

Our Cold/Flu system releases these combination of compounds every 2hours throughout the night, with a higher dosage of compounds beingreleased in the morning to combat these proven middle of the night andearly morning symptoms, which are the worst of the day.

Cold and flu symptoms are worst in the middle of the night and earlymorning because the hormone cortisol, a key inflammation fighter, ismissing at that time. Our system utilizes its core competitive advantageby preprogramming our System to release more medicaments precisely atthat time to offset these peak symptoms. Current cold and flumedications end up losing efficacy by early morning when cold symptomspeak, so the user either has sleep cut short due to the onset of thesesymptoms, or wakes up out of slumber feeling sick with peak symptoms.Our system will ensure that a while a person is actually sleeping, asufficient dose of cold and flu medicine is freshly delivered to offsetthese peak morning symptoms.

Applications—Weight Control, Vitamin and Herbal Supplementation

In yet another application, a series of weight loss vitamins andsupplements is administered in small distinct doses many times over amultiple day period. Vitamins and supplements are absorbed by the bodyin small dosages. Contrary to popular belief, once-a-day products arenot maximally effective because excess dosages are excreted unused. Thisimplementation of the present invention precisely controls the timingand dosage of small but distinct amounts of vitamins and supplementsduring a 24 hour period to ensure that vitamins and supplements areconstantly bio-available for optimal absorption and cellular function.Greater doses are automatically released prior to mealtimes to counterappetite cravings, resulting in a much more effective diet program.

Applications—Angina

Research shows that variant angina occurs 30 times more often between2:00 a.m. and 4:00 a.m. (‘critical angina phase’) than at any other timeof the day. Nitroglycerin effectively combats angina attacks, ifadministered in optimal doses. Current nitroglycerin patches exist, butthey can only release a constant amount of nitroglycerine steadily overtime. Current patches cannot tailor the release of nitroglycerine tooptimize treatment by releasing more nitroglycerine precisely during thecritical angina phase to offset these peak symptoms.

In addition, nitroglycerine loses its effectiveness and requires higherand higher dosages when administered constantly. Our bodies becometolerant to it. Current systems cannot stop or decrease the release ofnitroglycerine when disease symptoms are lowest. Thus, these current‘dumb’ patches cannot offset the critical angina phase by releasing moreof the drug, nor can they shut down or stop nitroglycerineadministration when the body doesn't need it. It is a ‘one dose fitsall’ type of scenario once each “dumb” patch is applied to the patient.

The method in accordance with the present invention utilizes anautomated transdermal system in order to transdermally administer morenitroglycerine during the critical angina phase to ensure adequateoffset of these symptoms and less nitroglycerine when it is not neededso that no tolerance builds up. Our method utilizes a ‘smart’ patchmedicine system at this time to offset these peak critical phases in thedisease cycle arising due to the human body's circadian rhythm.

The preprogrammable automated transdermal system is worn around thewrist like a watch (or the forearm arm or ankle) and releasesnitroglycerine in optimal dosages at times that are optimallysynchronized. This is pursuant to a preprogrammed and tailored dosageprofile. Current nitroglycerin patches only have the capability torelease a constant dose of nitroglycerin over a period of time. Currentnitroglycerin patches simply cannot alter or vary dosages to increasedosages at different times of the day, and decrease dosages at othertimes of the day.

The nitroglycerin system in accordance with the present invention hasthree primary advantages over current nitroglycerin patches. First, thesystem utilizes its core competitive advantage to automatically andprecisely release nitroglycerin in peak amounts to offset the peaksymptoms of morning attacks occurring during the critical angina phase.Current nitroglycerine patches have release rates that stay constant anddo not increase to offset critical phases, and do not decrease assymptoms decrease. Second, our system solves the tolerance issue byreleasing less (or no) nitroglycerin in off-peak hours, and thenreleasing nitroglycerin at just the right time so that it is presentduring critical periods, without increasing tolerance. Third, our systemaccomplishes 1 and 2 above automatically, without the need for a patientto wake up to take a drug at this critical phase, which does away withthe need for any increased patient compliance.

As a result we believe that our nitroglycerin system represents an idealdelivery system for patients who use nitroglycerin regularly for thetreatment and/or the prevention of heart attacks and strokes. Patientcompliance regarding the timing and dose of heart attack medication iscrucial. Patient non-compliance with physician's instructions for thisis often a cause of re-hospitalization, according to the US Departmentof Health and Human Services. The system solves this problem, and willdecrease the need for re-hospitalization by dramatically increasingpatient compliance.

This system can be either an ‘wear each night and remove in the morning’system, whereby it only releases nitroglycerine automatically to offsetthe critical angina phase in the morning, or a ‘total solution’ system,that is worn for a period of 24 hours to several days, and thatadministers nitroglycerine in tailored amounts and at tailored times assynchronized with the body's circadian rhythm (and conveniently takenoff while showering or swimming).

The system is an innovative new drug therapy for angina. With itssuperior advantage of optimized and automated time and doseadministration synchronized with our circadian rhythms, the system inaccordance with the present invention ensures that nitroglycerin willcirculate in the bloodstream exactly when the patient needs it, andwithout any build up tolerance. For these reasons, our system issuperior to current steady release nicotine patches. Our system'sincreased advantages are extremely relevant for those patients withmoderate to severe angina.

FIG. 7 shows an exemplary administration profile for a nitroglycerinedelivery system tailored to treat variant angina attacks or anginapectoris. This type of angina attack has a peak frequency in manypatients between the hours of 2:00 and 4:00 AM. This is a particularlydifficult time to wake up to take a drug such as nitroglycerine. Inaccordance with the present invention an administration profilesubstantially like that shown in FIG. 7 is automatically administered.In FIG. 7 the vertical axis indicates blood plasma level in nanogramsper milliliter, and the horizontal axis indicates time from 10:00 PMthrough the night to 8:00 AM.

FIG. 8 illustrates an exemplary administration profile for anitroglycerine delivery system tailored to treat stress-induced anginaattack. In FIG. 8 the vertical axis indicates blood plasma level innanograms per milliliter, and the horizontal axis indicates time from12:00 AM through the day until about 4:00 PM. The administration profileshown in FIG. 8 provides a high blood plasma concentration throughoutthe waking hours of a day when stress is likely occur.

Applications—Asthma

The automated transdermal asthma system automatically administers amorning dose of albuterol, tolobuterol, salmeterol, beta 2 agonist orany other antiarrhythmic drug (an ‘Asthma drug’) to combat the peaksymptom of morning asthma attacks known as the ‘morning dip’.

Asthma attacks occur 100 (one hundred) times more often between thehours 4 A.M. and 6 A.M., when most people are asleep. This is due to theearly morning deterioration of respiratory function known as ‘morningdip’, which is the time of day that respiratory function is at itslowest. These early morning asthma attacks cause great distress tosufferers and care providers. The morning dip represents the dip inrespiratory function at this time when asthma attacks are 100 times morelikely to occur. Our system effectively combats the morning dip byreleasing more Asthma drug at this time to offset this peak morningsymptom. In other words, our ‘smart’ patch varies the level of drug inthe bloodstream so that drug concentrations are highest when respiratoryfunction is at its lowest.

Current ‘dumb’ asthma patches exist, but they can only release aconstant amount of drug steadily over time. Current patches cannottailor the release of drug to optimize treatment by releasing more drugprecisely during the morning dip to offset these peak critical symptoms.

The Asthma system has two primary advantages over current patches.First, the system of the present invention utilizes its core competitiveadvantage to automatically and precisely release albuterol or otherasthma drugs in peak amounts to offset the peak symptoms associated withthe morning dip. Current patches have release rates that stay constantand do not increase to offset this peak critical phases, and do notdecrease as symptoms decrease. Second, our system accomplishes 1 and 2above automatically, without the need for a patient to wake up to take adrug at this critical phase, which does away with the need for anyincreased patient compliance.

The automated transdermal system for Asthma is worn around the wristlike a watch (or the forearm arm or ankle) and releases albuterol orother Asthma drugs in optimal dosages at times that are optimallysynchronized, especially to offset the morning dip, pursuant to apreprogrammed and tailored dosage profile. Current Asthma patches onlyhave the capability to release a constant dose over a period of time.Current Asthma patches simply cannot alter or vary dosages to increasedosages at different times of the day, and decrease dosages at othertimes of the day.

The system is an innovative new drug therapy for asthma. With itssuperior advantage of optimized and automated time and doseadministration synchronized with our circadian rhythms, our systemensures that albuterol or another asthma drug will circulate inincreased amounts in the bloodstream exactly when the patient needs it.For these reasons, our system is superior to current steady releasepatches. Our system's increased advantages are extremely relevant forthose patients with moderate to severe asthma.

Applications—Hypertension

The clondine automated transdermal system utilizes clondine, (or anotherhypertension drug) an effective drug that combats high blood pressure.The clondine automated transdermal drug delivery system has an automatedmorning release of clondine to combat the peak symptom of morning heartattacks.

Blood pressure differs at different times of the day. Blood pressuresurges upon waking, and is lower by 20 to 30 percent while sleeping. Ourpreprogrammed automatic transdermal system utilizes its core competitiveadvantage by releasing clondine in a tailored fashion to counter highblood pressure when symptoms are highest, while releasing less clondinewhen symptoms are less severe.

Current clondine patches release the drug consistently over time. Itcannot release more of the drug when symptoms are worst. People die mostwhen the symptoms peak. Having the advantage of administering more ofthe drug when a patient needs it the most can mean the differencebetween life and death, especially in patients with moderate to severehigh blood pressure.

The automated transdermal system for hypertension has two primaryadvantages over current patches. First, our system utilizes its corecompetitive advantage to automatically and precisely release clondine orother hypertension drugs in peak amounts to offset the peak symptomsassociated with the dangerous morning symptoms. Current hypertensionpatches have release rates that stay constant and do not increase tooffset this peak critical phases, and do not decrease as symptomsdecrease. Second, our system accomplishes 1 and 2 above automatically,without the need for a patient to wake up to take a drug at thiscritical phase, which does away with the need for any increased patientcompliance.

Applications—Depression, Alzheimer's, Attention Deficit

The selegiline automated transdermal system utilizes selegiline, aneffective MAO inhibitor for the treatment of depression, Alzheimer's andAttention Deficit Disorder.

The selegiline automated transdermal drug delivery system gives anautomated morning release of selegiline to combat the peak symptom ofmorning depression without the side effect of sleep disturbances.

The system in accordance with the present invention is applied beforebed. It does not release the drug until an hour or 2 before morning, sosymptom of morning depression would be corrected by our system withoutsubjecting the patient to sleep disturbances.

Primary negative side effects of the selegiline patches are abnormaldreams, insomnia, and difficulty sleeping. We believe that byspecifically refraining from administering selegiline at night, andutilizing our system's core competitive advantage to turn it on an houror so before waking, we can do away with this negative side effect andstill offset the critical phase of morning symptoms of depression. Ithas been reported that patients have increased symptoms of depressionupon waking if the critical amount of Selegiline is not circulatingthrough their system. Our system utilizes its core competitive advantageto provide a compelling solution to this problem. Our system is appliedbefore bed, it would not release the drug until an hour or two beforemorning, so symptom of morning depression would be corrected by oursystem without subjecting the patient to sleep disturbances.

Current Oral Selegiline produces horrible side effects. There is a newSelegiline patch coming out on the market, but it to produces sleepdisturbances. It is believed that the system in accordance with thepresent invention would be superior to conventional Selegiline productdelivery systems.

Applications—In General

The present invention is particularly useful in applications in which itis necessary and/or desirable to start the administration of a drug,stop the administration of a drug, and/or increase/decrease the dosageof a drug at a time when it is inconvenient or impossible for a patientto initiate the necessary actions. This is particularly useful for awide variety of drug administration applications that benefit whenadministration is started, stopped, or changed while a person issleeping. As chronotherapy knowledge increases, it is contemplated thata wide variety of applications will be discovered in which benefit isrealized by starting, stopping and/or changing the drug administrationwhile a patient sleeps.

In each of the examples, treatment is continued as needed to providesuperior symptomatic relief, prevent exacerbation of symptoms, and/orprevent and/or delay progression of the disease state or condition inthe patient, or until it is no longer well tolerated by the patient, oruntil a physician terminates treatment. For example, a physician maymonitor one or more symptoms and/or serum levels of active materialand/or metabolic by-product(s) in a patient being treated according tothis invention and, upon observing attenuation of one or more symptomsfor a period of time, conclude that the patient can sustain the positiveeffects of the above-described treatment without further administrationfor a period of time. When necessary, the patient may then return at alater point in time for additional treatment as needed.

As used herein, ‘day’ means a 24-hour period. Thus, for example, ‘for atleast three consecutive days’ means for at least a 72-hour period.During or after the treatment, a physician may monitor one or moresymptoms and/or serum levels in the patient and, upon observing animprovement in one or more of the parameters for a period of time,conclude that the patient can sustain the positive effects of thetreatment without further administration of the active material for aperiod of time.

In order to use an active material for therapeutic treatment (includingprophylactic treatment) of mammals including humans according to themethods of this invention, the active material is normally formulated inaccordance with standard pharmaceutical practice as a pharmaceuticalcomposition. According to this aspect of the invention there is provideda pharmaceutical composition comprising an active material inassociation with a pharmaceutically acceptable diluting substance orcarrier, wherein the active material is present in an amount foreffective treating or preventing a particular condition. Whileindividual needs may vary, determination of optimal ranges for effectiveamounts of an active ingredient (alone or in combination with otherdrugs) within the ranges disclosed herein is within the expertise ofthose skilled in the art. Accordingly, ‘effective amounts’ of eachcomponent for purposes herein are determined by such considerations andare amounts that improve one or more active ingredient functions and/orameliorate on or more deleterious conditions in patients and/or improvethe quality of life in patients.

The present invention also provides pharmaceutical kits for treating aparticular symptom, condition and/or disease and/or improving aparticular biological function, comprising one or more containerscomprising one or more active compositions in accordance with thisinvention. Such kits can also include additional drugs or therapeuticsfor co-use with the active composition for treatment or prevention of aparticular symptom, condition and/or disease and/or improving aparticular biological function. In this embodiment, the activecomposition and the drug can be formulated in admixture in onecontainer, or can be contained in separate containers for simultaneousor separate administration. The kit can further comprise a device(s) foradministering the compounds and/or compositions, such as device 100shown in FIG. 1, and written instructions in a form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which instructions can alsoreflect approval by the agency of manufacture, use or sale for humanadministration.

Although the invention has been described and illustrated with a certaindegree of particularity, it is understood that the present disclosurehas been made only by way of example, and that numerous changes in thedosages, administration profiles, timing, as well as the combination andarrangement of parts can be resorted to by those skilled in the artwithout departing from the spirit and scope of the invention, ashereinafter claimed.

1. A method of delivering nicotine to a subject, the method comprising:wearing an automated transdermal drug delivery device during thesubject's sleep such that a permeable membrane of the automatedtransdermal drug delivery device is in contact with skin of the subject;and beginning to deliver a substance comprising nicotine from areservoir of the transdermal drug delivery device to the permeablemembrane during a one hour period immediately prior to the subject'swaking to transdermally administer nicotine to the subject.
 2. Themethod of claim 1 further comprising delivering the substance from thereservoir to the permeable membrane at a plurality of timescorresponding to expected nicotine cravings of the subject.
 3. Themethod of claim 2 wherein the plurality of times correspond to mealtimes of the subject.
 4. The method of claim 1 wherein the reservoir isa pressurized reservoir.
 5. The method of claim 4 further comprisingmoving the substance from the pressurized reservoir to the permeablemembrane through an electronically controlled valve.
 6. The method ofclaim 1 further comprising replacing the reservoir after depletion. 7.The method of claim 1 further comprising moving at least a portion ofthe substance delivered to the permeable membrane into a waste reservoirto cease transdermal administration of nicotine.
 8. The method of claim1 wherein the substance comprises nicotine dissolved in a solvent, themethod further comprising moving solvent from the permeable membraneinto a solvent recovery element.
 9. The method of claim 1 wherein thepermeable membrane is coated with an adhesive.
 10. A method ofdelivering nicotine to a subject, the method comprising: wearing anautomated transdermal drug delivery device such that a permeablemembrane of the automated transdermal drug delivery device is in contactwith skin of the subject; delivering a substance comprising nicotinefrom a reservoir of the transdermal drug delivery device to thepermeable membrane at a plurality of times corresponding to expectednicotine needs of the subject to transdermally administer nicotine tothe subject; and moving at least a portion of the substance delivered tothe permeable membrane into a waste reservoir to cease transdermaladministration of nicotine.
 11. The method of claim 10 wherein one ofthe plurality of times comprises a time prior to an expected waking timeof the subject.
 12. The method of claim 10 wherein the plurality oftimes comprise expected meal times of the subject.
 13. The method ofclaim 10 wherein the reservoir is a pressurized reservoir.
 14. Themethod of claim 13 further comprising moving the substance from thepressurized reservoir to the permeable membrane through anelectronically controlled valve.
 15. The method of claim 10 furthercomprising replacing the drug reservoir after depletion.
 16. The methodof claim 10 further comprising moving at least a portion of thesubstance delivered to the permeable membrane into a waste reservoir tocease transdermal administration of nicotine.
 17. The method of claim 10wherein the substance comprises nicotine dissolved in a solvent, themoving step comprising moving solvent from the permeable membrane into asolvent recovery element.
 18. The method of claim 10 wherein thepermeable membrane is coated with an adhesive.